Memory T lymphocytes are characterized by their ability to exhibit a rapid response to the recall antigen. Our previous study shows that histone methylation provides a chromatin basis for the rapid transcriptional response of memory CD8 T cells. To further understand how the histone methylation patterns are established and maintained in memory T cells, we conducted a parallel analysis of gene expression changes with histone methylation changes in nave and memory (central and effector memory cells) CD8 T cells after in vitro stimulation. Nave, central memory and effector memory CD8 T cells were isolated from normal adult and stimulated in vitro with antibodies against CD3 and CD28. Gene expression changes were analyzed by microarray and histone methylation (H3K4me3 and H3K27me3) was analyzed by ChIP-Seq. As expected, we observed substantial changes in gene expression (25% increase and 25% decrease of total expressed genes) after 72 hours of stimulation, activation. In parallel, we observed similar trend of histone methylation (H3K4me3 and H3K27me3) changes in corresponding genes in CD8 T cells. Furthermore, we found that the open chromatin of some poised genes in memory CD8 T cells were established in activated nave CD8 T cells, suggesting that activation is a necessary step of convert the memory cell type of chromatin in nave cells. Together, these results indicate that histone methylation is dynamic after activation in CD8 T cells and suggest that activation-induced change of chromatin in nave T cells is part of differentiation process to establish memory T cells.